Proceedings of the National Academy of Sciences of the United States of America

Volume | Issue number

113 | 5

Pages (from-to)

E587-E596

Document type

Article

Faculty

Faculty of Dentistry (ACTA)

Abstract

Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic
latent infection. The lymphotropic Epstein-Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription
of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact
with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed
that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA
via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized
by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viraland exosomal target. Using
an EBER-deficient EBV strain, enzymatic removal of 5'ppp, in vitro transcripts, and coculture experiments, we established
that 5'pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer
from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We
detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non-cell-autonomous
EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes
have a physiological role in the host-pathogen stand-off and may promote inflammatory disease.

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